Lung cancer is the leading cause of cancer death in the United States and worldwide. Majority of lung cancer patients require radiation as part of their treatment. Despite advances in radiation technology, treatment outcomes remain poor, with an overall cure rate of less than 10-15% and moderate toxicity in 10-30% of treated patients. Despite individual difference in their treatment outcome, the treatment is lack of individualization as there is no reliable way to predict which patient will have the cancer controlled and which patient will develop toxicity as a result of receiving a particular dose of radiation therapy to treat their lung cancer. Our preliminary results demonstrated that the during treatment PET scan was correlated with post-treatment response and long-term survival, and V/Q SPECT changed significantly during treatment, and the changes of SPECT and blood markers were predictive of late response. In the proposed clinical trial, we will validate above findings and use them during PET to guide individualized adaptive radiation dose escalation. We will enroll patients who have been diagnosed with non-small-cell lung cancers and are planning to receive radiation therapy as a part of their treatment. At midway during their course of radiation treatments, each patient will undergo PET/CT scan for measuring tumor activity/size and V/Q SPECT scan for mapping lung function. At three points during their course of radiation treatments, each patient will have blood drawn for markers. The results of these tests will be analyzed to determine their ability to accurately predict both the chance of long-term tumor control and the risk for developing lung toxicity. In the late phase of the grant period, we will further adapt the radiation treatment by the use of V/Q SPECT and blood marker during treatment so that the treatment gain could be maximized in each patient. PUBLIC HEALTH RELEVANCE: This study will identify markers to predict treatment outcome for patients with lung cancer. This project will also study the potential for personalized care to improve treatment outcome.